Critically ill patients with sepsis, trauma and other serious medical conditions often develop multiple organ dysfunction syndrome (MODS) with high mortality rate (30-80%). There is no specific therapy to prevent or cure MODS beyond treatment of the underlying illness. Emerging evidence suggests that oxidative stress- induced endothelial activation in vital organs is a key step in the pathology as it leads to exacerbated inflammatory cell infiltration and tissue damage. Unfortunately, general antioxidants with no target specificity have failed in clinical trials. On the contrary, exercise training induces profond adaptations in skeletal muscle and other organs and confers significant protection. We have obtained new evidence in mice supporting a protective role of extracellular superoxide dismutase (EcSOD) from skeletal muscle, which has a heparin- binding domain for targeting endothelial cells. Exercise trained mice and muscle-specific EcSOD transgenic mice are protected from endotoxemia, a condition leads to MODS. We hypothesize that enhanced EcSOD expression in skeletal muscle protects against MODS by reducing endothelium oxidative stress and activation in peripheral vasculature. We propose two specific aims to test this hypothesis: 1) To determine if muscle-derived EcSOD mediates protection against MODS; and 2) To define the mechanism by which muscle- derived EcSOD inhibits endothelial cell activation and inflammatory cell-endothelial cell interaction. These aims are hypothesis-driven and based on evidence from the literature and our preliminary findings. We will use state-of-the-art approaches in clinically relevant animal models to elucidate a novel non-contractile function of skeletal muscle-derived antioxidant against a serious disease condition.